Studying the genes of people with psoriasis and psoriatic arthritis offers the promise of new treatments

People with severe psoriasis spend up to six hours a day at the Psoriasis Day Care Center at the University of California, San Francisco. They receive ultraviolet light treatments and coat their psoriasis plaques with coal tar ointment. The process is messy, cumbersome and tedious. For most of these patients, other therapies have failed to help.

During his medical residency at the center, Dr. Wilson Liao formed a deep sense of connection to his patients. "When you are there with people for hours, you learn how psoriasis impacts their lives, their struggles, their hopes," he said. "It's much different than an office visit."

Inspired by these patients, Liao decided to dedicate his career to understanding psoriasis.

Now an assistant professor in the dermatology department at UCSF, he is one of a growing cadre of researchers working to unravel the intricate connections between genes, the immune system and skin cells. Their discoveries may eventually mean safer, more effective therapies for psoriasis and psoriatic arthritis.

40 years of genetics research

Although the first major genetic "hotspot" related to psoriasis was identified nearly four decades ago, it was the sequencing of the human genome in 2003 that allowed scientists to systematically compare the genes of people with psoriasis to those of healthy people.

Sequencing has helped pinpoint genes involved in psoriasis—and has revealed the immense complexity of the disease's origins.

Dr. J.T. Elder, director of the Psoriasis Genetics Laboratory at the University of Michigan Department of Dermatology, is a pioneer in the field. So far, he and other researchers around the U.S. and worldwide have found approximately 25 genes that influence the risk of developing psoriasis.

"Presumably there are hundreds if not thousands of genes that cooperate," Elder explained. "Often no one gene controls the show. People have a hard time getting their arms around this, because we think of something catastrophically wrong with one gene. But basically that's not the way it works in the new genetics. It's the cumulative effect of many small differences."

Foundation Tissue Bank plays a role

Researcher Anne Bowcock has been trying to find the pathways by which differences in genes lead to psoriasis and psoriatic arthritis. In an important development, Bowcock and her team have traced one such pathway using DNA samples from several members of one family, all of whom have psoriasis.

Bowcock obtained the DNA samples from the Psoriasis Foundation's National Psoriasis Tissue Bank and the National Psoriasis Victor Henschel BioBank. She and her research team plan to publish the study later this year.

Bowcock, a professor of genetics at Washington University School of Medicine in St. Louis, offers an example of how genes can lead to psoriatic disease: "Some cells produce proteins or enzymes that send signals to other cells. A protein that is expressed more highly than normal might tell an immune cell to be more active or might keep a skin cell from (reaching its final stage of development)."

In this case, researchers try to trace the overexpressed protein back to a gene that might be giving faulty instructions. These routes are often very complex.

The great thing about genetics is that it gives you a trigger, something that is going on at the start of the process," Bowcock said. "If you can understand the pathway, you can develop novel treatments to interfere with it."

Bowcock and Michigan's J.T. Elder say that most of the genetic pathways implicated in psoriasis so far appear to involve activation of the immune cells and the signals those cells send to the skin.

Matching genes to disease features

A professor of dermatology at the University of Utah, Dr. Gerald Krueger has been researching psoriasis since 1972. He is not a geneticist, but worked with Bowcock, Elder and other researchers on the first major push to identify psoriasis-related genes.

Now Krueger's team at the university is focusing on associating specific genes with how psoriasis shows up in the body.

Over the last nine years, Krueger and his colleague, Dr. Kristina Callis Duffin, have carefully catalogued the psoriasis of more than 1,200 participants in a study called the Utah Psoriasis Initiative. The team records more than 300 pieces of information about each patient and takes a DNA sample.

By analyzing the DNA and then tracking changes in the patients' psoriasis over time, the team hopes to see whether people with similar genetic changes also show similarities such as where psoriasis appears on their bodies, the way they respond to a particular treatment or the way their psoriasis behaves during pregnancy.

As technology advances, researchers are able to find genes that increase or decrease the risk of having psoriasis. But these so-called "modifier genes" are only part of the story, says UCSF researcher Liao. "We believe there are other genes that we haven't yet discovered called the 'trigger genes.' We are now using (newer technology) to identify these trigger genes in individual patients."

This new technology is not only more precise, but also much less expensive. The original human genome project, which "mapped" all of the genes that people have in their cells, cost hundreds of millions of dollars. Today scientists can analyze one person's DNA for around $10,000.

Linking genetics to treatment

Ultimately, psoriasis could be the first disease that uses "personalized medicine," which would use a patient's genetic information to tailor a treatment specifically for that person, says Utah's Gerald Krueger. By using the genetic information researchers have been collecting from patients, "we will know over the period of many years which drugs they respond to and which they don't."

Wilson Liao estimates that within five to 10 years, scientists' understanding of "trigger genes" will allow doctors to predict how individual patients will respond to medications. However, he and other researchers say that creating new medicines based on genetic information is further down the road.

"I think there will be a lot of new drugs as a result of genetic findings, eventually," agrees Anne Bowcock. "That has always been the goal—targeted therapy without side effects."